Project Summary Diabetes mellitus (DM) remains an incurable disease that is poised to increase in the next two decades. Management of DM is mediated primarily by insulin therapy, which depends on patients monitoring their blood glucose levels. However, due to lack of patient compliance, inaccuracies of strip sensors, and inability to test for long periods such as during sleep, patients experience hyper- and hypo-glycemic episodes. Continuous glucose monitoring from indwelling sensors holds the promise of a closed loop insulin delivery system. Despite significant improvements in sensor design and overall accuracy, obstacles towards the long-term successful application of such sensors remain. These include the need for miniaturization to minimize tissue injury without a loss in sensitivity/ accuracy, biofouling, and the foreign body response (FBR). Approaches to improve sensor function include delivery of tissue modifiers to modulate inflammatory responses. However, to date the longevity of indwelling sensors is limited to 3-14 days and the inclusion of biologics to sensors complicates manufacturing and creates additional regulatory burdens. Therefore, a biomaterial-based approach to modulate the FBR and improve sensor function represents an attractive solution. In this application, we propose the generation of a novel glucose sensor coating based on bulk metallic glass (BMG). BMGs are metallic alloys with an amorphous atomic structure that combine high corrosion resistance and polymer-like processability. Specifically, we propose to systematically evaluate Platinum or Zirconium based BMG chemistries and geometries to develop a bio-protective surface for an indwelling glucose sensor. Accordingly, the specific aims of this application are: 1) to screen BMG libraries for desirable material properties and biological responses; 2) to identify BMG topographical features capable of favorably modulating in vivo responses; and 3) to integrate BMG topographical features to enhance sensor function. Such bio-protective surfaces could be used to shield virtually any biomedical implant from adverse biological reactions, thereby improving implant function and lifespan.